Intermediates useful in solid phase synthesis method

ABSTRACT

A solid phase synthesis method and intermediates useful in the process are disclosed for the preparation of diamino diol and diamino alcohol inhibitors of HIV protease.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/001,605, filed Jul. 28, 1995, which is incorporatedherein by reference.

TECHNICAL FIELD

The present invention relates to a solid phase synthesis method usefulfor preparing compounds which are inhibitors of HIV protease. Thepresent invention also relates to intermediates which are useful in thesolid phase synthesis method.

BACKGROUND OF THE INVENTION

Drug discovery research involves the screening of large numbers ofchemical compounds before a drug candidate is identified. One factorlimiting the success of this process is the ability to rapidlysynthesize compounds for testing in various screening assays. Recentadvances in high through-put screening have increased the need forimproved methods for rapid synthesis of compounds for testing.

Methods for solid phase synthesis of peptides have been used for manyyears to rapidly prepare peptides of various size and composition.Application of this technology to non-oligomeric small organic moleculescould provide a method for rapid synthesis of large numbers ofcompounds. However, because such small organic molecules are notoligomeric and they frequently do not contain functional groups whichlend themselves to coupling to solid phase supports, solid phasesynthetic methods are not readily applicable.

HIV protease inhibitors are known to be useful for inhibiting HIVprotease and for inhibiting an HIV infection in humans. The HIV proteaseinhibitors are an example of a class of compounds for which it is notobvious how solid phase synthetic methods can be readily applied.

In particular, the classes of HIV protease inhibitors represented byA77003 and A80987, and the like, present challenges for solid phasesynthetic methods because (1) these molecules do not contain afunctional group (typically, a carboxyl group) which can be used toattach the molecule to a solid support and (2) these molecules extend inboth directions from the central diamino diol or diamino alcohol coreunit, which is contradictory to the conventional unidirectional solidphase synthesis methods used to prepare peptides. ##STR1##

The HIV protease inhibitors A77003 and A80987 are disclosed in U.S. Pat.No. 5,142,056, issued Aug. 25, 1992 and U.S. Pat. No. 5,354,866, issuedOct. 11, 1994, respectively, both of which are incorporated herein byreference.

It has now been discovered that HIV protease inhibitors of the typesrepresented by A77003 and A80987 can be readily synthesized using solidphase methods.

DISCLOSURE OF THE INVENTION

In accordance with the present invention, there are compounds of theformula IA: ##STR2## wherein R₁ and R₂ are independently selected fromphenyl, substituted phenyl, loweralkyl and cycloalkyl; R₃ is hydrogen orloweralkyl; L₁ is alkylene; P₁ and P₂ are the same or differentN-protecting groups; and P₃ is hydrogen or a carboxy protecting group;or a salt thereof.

Preferred compounds of the formula IA are compounds of the formula IB:##STR3## wherein R₁, R₂, R₃, L₁, P₁, P₂ and P₃ are as defined above.

Preferred compounds of formula IA and IB are those wherein R₁ and R₂ arephenyl, R₃ is C₁ -C₃ alkyl and L₁ is --(CH₂)_(n) -- wherein n is 2-6.

Even more preferred compounds of formula IA and IB are those wherein R₁and R₂ are phenyl, R₃ is methyl and L₁ is --(CH₂)₂ -- and P₁ and P₂ areindependently selected from 9-fluorenylmethoxycarbonyl, allyloxycarbonyland (2-trimethylsilyl)ethoxycarbonyl and P₃ is hydrogen.

Compounds of the formula I can be prepared as shown in Scheme 1. Thepreferred compounds of the formula IB are shown as examples. Diol 1 isreacted with aldehyde or ketone 2 in the presence of an acid (forexample, sulfuric acid) to give IB. In diol 1, the N-protecting groupscan be the same or different. For example, they can both bebenzyloxycarbonyl (Cbz) groups. The Cbz groups can be removed (forexample, by hydrogenation) and replaced with other N-protecting groups(for example, 9-fluorenylmethoxycarbonyl and the like) prior to couplingof IB (wherein P₃ is hydrogen) to a solid support (resin). Suitableresins include hydroxymethylphenoxymethyl resin (HMP resin or Wangresin), 4-methylbenzhydrylamine resin (MBHA resin), benzhydrylamineresin (BHA resin), chloromethyl resin (Merrifield resin) and the like. Apreferred resin is NovaBead MBHA (4-methylbenzhydrylamine) resin(NovaBiochem, LaJolla, Calif.). ##STR4##

The compound of formula IA or IB can be used to prepare A77003 oranalogs thereof by coupling IA or IB (wherein P₃ is hydrogen) to a solidsupport (resin) via an ester or an amide linkage (see Scheme 2 whereinIB is used as a specific example). A preferred coupling to a resin isvia an amide bond. The N-protecting groups P₁ and P₂ are removed at thesame time or separately and the left-hand and right-hand portions of themolecule are sequentially coupled to the core. For example, first anamino acid (AA₁) is coupled to each end using standard peptide couplingmethodology, and then a terminating group (for example, a carboxylicacid (denoted by R--CO₂ H)) is coupled to each end of the molecule usingstandard peptide coupling methodology. When P₁ and P₂ are different,selective deprotection allows different amino acids and differentcarboxylic acids to be added to each end of the core, resulting innon-symmetrical products. Acid-mediated cleavage (for example, withtrifluoroacetic acid or the like) provides the desired product (7).##STR5##

Also in accordance with the present invention, there are compounds ofthe formula IIA: ##STR6## wherein R₄ and R₅ are independently selectedfrom phenyl, substituted phenyl, loweralkyl and cycloalkyl;

L₂ is

(a) alkylene,

(b) --O--((CH₂)₂ --O)_(m) CH₂ -- wherein m is 1-10 or ##STR7## P₄ and P₅are the same or different N-protecting groups; and P₆ is hydrogen or acarboxy protecting group; or a salt thereof.

Preferred compounds of the formula IIA are compounds of the formula IIB:##STR8## wherein R₄, R₅, L₂, P₄, P₅ and P₆ are defined as above.

Preferred compounds of formula IIA and IIB are those wherein R₄ and R₅are phenyl and L₂ is --(CH₂)_(p) -- wherein p is 1-10 or --O--((CH₂)₂--O)_(m) --CH₂ -- wherein m is 2-6.

Even more preferred compounds of formula IIA and IIB are those whereinR₄ and R₅ are phenyl, L₂ is --(CH₂)₉ -- or --O--((CH₂)₂ --O)₂ --CH₂ --and P₄ and P₅ are independently selected from9-fluorenylmethoxycarbonyl, allyloxycarbonyl and(2-trimethylsilyl)ethoxycarbonyl and P₆ is hydrogen or allyl.

Also preferred are compounds of formula IIA and IIB wherein when P₆ is acarboxy protecting group, the carboxy protecting group can beselectively removed while retaining the N-protecting groups P₄ and P₅.

Also in accordance with the present invention, there are compounds ofthe formula III:

    CH.sub.2 ═CH--O-L.sub.2 -CH.sub.2 --CO.sub.2 P.sub.6   III

wherein

L₂ is

(a) alkylene,

(b) --O--((CH₂)₂ --O)_(m) --CH₂ -- wherein m is 1-10 or ##STR9## and P₆is hydrogen or a carboxy protecting group.

Preferred compounds of formula III are those wherein L₂ is --(CH₂)_(p)-- wherein p is 1-10 or --O--((CH₂)₂ --O)_(m) --CH₂ -- wherein m is 2-6.

Even more preferred compounds of formula III are those wherein L₂ is--(CH₂)₉ -- or --O--((CH₂)₂ --O)₂ --CH₂ -- and P₆ is hydrogen or allyl.

Compounds of the formula III can be prepared as shown in Scheme 3.Carboxylic acid 8 is esterified (a preferred P₆ is allyl) to give ester9. Reaction of 9 with ethyl vinyl ether and mercury acetate gives vinylether III. ##STR10##

Compounds of formula II can be prepared as shown in Scheme 4 (using IIBas a specific example). Alcohol 10 is reacted with vinyl ether III inthe presence of an acid catalyst (for example, pyridinium p-toluenesulfonate) to give IIB. ##STR11##

The compounds of formula IIA and IIB can be used to prepare A80987 oranalogs thereof by coupling IIA or IIB (wherein P₆ is hydrogen to asolid support (resin) via an ester or amide linkage (see Schemes 5-6wherein IIB is used as a specific example). A preferred coupling to aresin is via an amide bond. The N-protecting groups P₄ and P₅ areremoved, at the same time or separately, and the left-hand andright-hand portions of the molecule are sequentially coupled to thecore. For example, first an amino acid (AA₁) is coupled to each endusing standard peptide coupling methodology and then a terminating group(for example, a carboxylic acid (denoted by R--CO₂ H)) is coupled toeach end of the molecule using standard peptide coupling methodology.When P₄ and P₅ are different, selective deprotection allows differentamino acids and different carboxylic acids to be added to each end ofthe core, resulting in non-symmetrical products. Acid-mediated cleavage(for example, with trifluoroacetic acid or the like) provides thedesired product (15).

To prepare non-symmetrical compounds directly analogous to A80987, onestarts with compound 11 wherein P₄ and P₅ can be selectively removed(for example, P₄ is 9-fluorenylmethoxylcarbonyl (Fmoc) and P₅ isallyloxycarbonyl). P₄ is removed and AA₁ is coupled, followed by R--CO₂H. Then P₅ is removed and R'--CO₂ H is coupled to give 19. ##STR12##

Compounds of the invention comprise asymmetically substituted carbonatoms. As a result, all stereoisomers of the compounds of the inventionare meant to be included in the invention, including racemic mixtures,mixtures of diastereomers, as well as single diastereomers of thecompounds of the invention. The terms "S" and "R" configuration, as usedherein, are as defined by the IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.

The term "loweralkyl" as used herein refers to straight or branchedchain alkyl radicals containing from 1 to 10 carbon atoms including, butnot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl,2,2-dimethylpropyl, n-hexyl and the like.

The term "cycloalkyl" as used herein refers to an alicyclic groupcomprising from 3 to 7 carbon atoms including, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "alkylene" as used herein refers to a straight or branchedchain carbon diradical containing from 1 to 10 carbon atoms including,but not limited to, --CH₂ --, --CH₂ CH₂ --, --CH(CH₃)CH₂ --, --CH₂ CH₂CH₂ --, and the like.

The term "substituted phenyl" refers to a phenyl group which issubstituted with one, two or three substituents independently selectedfrom loweralkyl, alkoxy, halo, thioalkoxy, amino, alkylamino,dialkylamino and hydroxyalkyl.

The term "hydroxyalkyl" as used herein refers to --OH appended to aloweralkyl radical.

The term "alkylamino" as used herein refers to a loweralkyl radicalappended to an NH radical.

The terms "alkoxy" and "thioalkoxy" as used herein refer to R₂₉ O-- andR₂₉ S--, respectively, wherein R₂₉ is a loweralkyl group.

The term "dialkylamino" as used herein refers to --NR₃₆ R₃₇ wherein R₃₆and R₃₇ are independently selected from loweralkyl groups.

The term "halo" or "halogen" as used herein refers to --Cl, --Br, --I or--F.

For the purpose of this application, the symbol P refers to either aprotecting group or the absence of a protecting group. An ordinarypractioner would know that phosphorus is a tri-valent or penta-valentatom and that lack of substituents thereto would indicate fiat the P₁,P₂, P₃, P₄, P₅, and P₆ designations in the specification and the claimshave meanings other than the symbol for phosphorus.

The term "carboxy protecting group" as used herein refers to acarboxylic acid protecting ester group employed to block or protect thecarboxylic acid functionality while the reactions involving otherfunctional sites of the compound are carried out. Carboxy protectinggroups are disclosed in Greene, "Protective Groups in Organic Synthesis"pp. 152-186 (1981), which is hereby incorporated herein by reference. Inaddition, a carboxy protecting group can be used as a prodrug wherebythe carboxy protecting group can be readily cleaved in vivo, for exampleby enzymatic hydrolysis, to release the biologically active parent. T.Higuchi and V. Stella provide a thorough discussion of the prodrugconcept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S.Symposium Series, American Chemical Society (1975), which is herebyincorporated herein by reference. Such carboxy protecting groups arewell known to those skilled in the art, having been extensively used inthe protection of carboxyl groups in the penicillin and cephalosporinfields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, thedisclosures of which are hereby incorporated herein by reference.Examples of esters useful as prodrugs for compounds containing carboxylgroups can be found on pages 14-21 of "Bioreversible Carriers in DrugDesign: Theory and Application", edited by E. B. Roche, Pergamon Press,New York (1987), which is hereby incorporated herein by reference.Representative carboxy protecting groups are C₁ to C₈ loweralkyl (e.g.,methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl;cycloalkyl and substituted derivatives thereof such as cyclohexyl,cylcopentyl and the like; cycloalkylalkyl and substituted derivativesthereof such as cyclohexylmethyl, cylcopentylmethyl and the like;arylalkyl, for example, phenethyl or benzyl and substituted derivativesthereof such as alkoxybenzyl or nitrobenzyl groups and the like;arylalkenyl, for example, phenylethenyl and the like; aryl andsubstituted derivatives thereof, for example, 5-indanyl and the like;dialkylaminoalkyl (e.g., dimethylaminoethyl and the like);alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl,valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl,1-(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1-ethyl,1-methyl-1-(propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyland the like; cycloalkanoyloxyalkyl groups such ascyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl,cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like;aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like;arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl,2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such asmethoxycarbonylmethyl, cyclohexyloxycarbonylmethyl,1-methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl, such asmethoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl,1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and thelike; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyland the like; alkylaminocarbonylaminoalkyl, such asmethylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such asacetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as4-methylpiperazinylcarbonyloxymethyl and the like;dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl,diethylaminocarbonylmethyl and the like;(5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as(5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and(5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.

The term "N-protecting group" or "N-protected" as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in Greene, "Protective Groups In Organic Synthesis," (JohnWiley & Sons, New York (1981)), which is hereby incorporated herein byreference. N-protecting groups comprise acyl groups such as formyl,acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl,2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl,o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such asbenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forminggroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl,(2-trimethylsilyl)ethyloxycarbonyl and the like; alkyl groups such asbenzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groupssuch as trimethylsilyl and the like. Preferred N-protecting groups are9-fluorenylmethoxycarbonyl, allyloxycarbonyl and(2-trimethylsilyl)ethyloxycarbonyl.

Salts of the compounds of the present invention indlude salts derivedfrom inorganic or organic acids. These salts include but are not limitedto the following: acetate, adipate, alginate, citrate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as loweralkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of the compounds of formula (I), or separately byreacting the carboxylic acid function with a suitable base such as thehydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia, or an organic primary, secondary ortertiary amine. Such pharmaceutically acceptable salts include, but arenot limited to, cations based on the alkali and alkaline earth metals,such as sodium, lithium, potassium, calcium, magnesium, aluminum saltsand the like, as well as nontoxic ammonium, quaternary ammonium, andamine cations, including, but not limited to ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like.

The foregoing may be better understood by reference to the followingexamples which are provided for illustration and are not intended tolimit the scope of the inventive concept.

EXAMPLE 1 (4R, 5R, 1"S)-1-Methyl-1-(3'-carboxypropyl)-4, 5-bis1"-(benzyloxycarbonyl)amino-2"-phenyl!ethyl-1,3-dioxolane

A suspension of(2S,3R,4S,5S)-2,5-di-(Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane (10.0g, 17.62 mmole; U.S. Pat. No. 5,142,056, issued Aug. 28, 1992) in 60 mLof levulinic acid and 0.8 mL of conc. H₂ SO₄ was stirred at ambienttemperature for 24-48 hours, or until the mixture turned into ahomogeneous yellow solution. The reaction mixture was taken up in 200 mLof ether and the solution was washed repeatedly with saturated NaClsolution to remove excess levulinic acid. Upon complete removal oflevulinic acid (TLC), the etheral solution was dried (MgSO₄), filtered,evaporated and dried in vacuo to give a white solid. 11.43 g, 97.3%. ¹ HNMR (CDCl₃) ¹ H NMR (CDCl₃): δ 1.40 (s, 3H), 2.0-2.1 (m, 2H), 2.35-2.50(m, 2H), 2.70-2.90 (m, 4H), 3.65-3.75 (m, 2H), 3.95 (m, 1H), 4.10 (m,1H), 4.70-5.00 (m, 6H), 7.00-7.30 (m, 20H); FAB-MS m/z 667 (M+H)⁺, 623(M-CO₂)⁺, base peak.

EXAMPLE 2 (4R, 5R, 1"S)-1-Methyl-1-(3'-carboxypropyl)-4, 5-bis1"-amino-2"-phenyl!ethyl-1,3-dioxolane

The product of Example 1 (11.4 g, 17.14 mmole) was hydrogenated in EtOAcor MeOH with 10% Pd/C as the catalyst at ambient temperature. Thecatalyst was filtered and washed extensively with MeOH. Concentration ofthe solution gave 6.64 g (97.2%) of a white solid. ¹ H NMR (MeOH-d₄): δ1.40 (s, 3H), 2.10 (m, 2H), 2.30 (m, 2H), 2.55-2.70 (m, 2H), 2.90 (d,2H), 3.10 (m, 1H), 3.45 (m, 1H), 3.95 (m, 1H), 4.10 (m, 1H), 7.10-7.40(m, 10H); CIMS m/z 399 (M+H)⁺, base peak.

EXAMPLE 3 (4R, 5R, 1"S)-1-Methyl-1-(3'-carboxypropyl)-4, 5-bis 1"-(fluorenylmethyloxy)carbonyl!amino-2"-phenyl!ethyl-1,3-dioxolane

To a solution of the product of Example 2 (3.79 g, 9.52 mmole), amixture of 55 mL of dioxane and 50 mL of water containing sodiumbicarbonate (1.639 g, 19.5 mmole) was added a solution of Fmoc-OSu(NovaBiochem, 6.48 g, 19.23 mmole) in 50 mL of dioxane over severalminutes. After stirring at ambient temperature overnight, water (300 mL)was added and the mixture was carefully acidified to pH 2 with 1N HCland extracted with EtOAC (5×100 mL). The combined organic solution wasworked up routinely and evaporated to give an off-white solid. Columnchromatography using 60% EtOAc in hexane as the solvent afforded 7.5 g(93.5%) of the title compound as a white solid. ¹ H NMR (MeOH-d₄): δ1.48 (s, 3H), 1.98 (d, 2H), 2.10 (t, 2H), 2.48 (m, 2H), 2.80 (m, 4H),3.90-4.15 (m, 8H), 6.8-7.8 (m, 26H). FAB-MS m/z 843 (M+H)⁺, 881 (M+K)⁺.

EXAMPLE 4A Allyl 10-Hydroxydecanoate

To a solution of 10-hydroxydecanoic acid (5.0 g, 26.5 mmole) and allylalcohol (15.5 g, 265 mmole) in 100 mL of CH₂ Cl₂ was added1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (SigmaChemical Co., 6.15 g, 31.8 mmole) and DMAP (100 mg). After stirring for2 h, the solution was washed with 0.1N HCl (3×50 mL), 5% aqueous NaHCO₃(3×50 mL), and brine (3×50 mL), then dried (MgSO₄), filtered andconcentrated. The crude product was passed through a silica gel plugusing 40% EtOAc in hexane to remove the baseline contamination.Concentration of the solution gave 4.5 g of an oil (75.0%). ¹ H NMR(CDCl₃): δ 5.92 (m, 1H), 5.32 (d.q, 1H), 5.23 (d.q, 1H), 4.58 (d.t, 2H),3.63 (t, 2H), 3.65 (T, 2H), 2.35 (t, 2H), 1.5-1.7 (m, 4H), 1.3 (m, 8H).CIMS (NH₃) m/z 229 (M+H)⁺, 246 (M+NH₄)⁺.

EXAMPLE 4B Allyl 10-Vinyloxydecanoate

Mercury acetate (2.44 g, 7.7 mmole) was added to a solution of allyl10-hydroxydecanoate (3.5 g, 15.4 mmole) in 80 mL of distilled ethylvinyl ether. The solution was purged with argon and refluxed under argonatmosphere overnight. After cooling to ambient temperature, K₂ CO₃ (1.0g) was added and the mixture stirred for 30 minutes. EtOAc (100 mL) wasadded and the solution was washed with saturated NaCl (4×80 mL), thendried ((MgSO₄), filtered and concentrated. The residue was purified bycolumn chromatography using 30% EtOAc-hexane as the solvent to give 3.0g of a liquid (61%). ¹ H NMR (CDCl₃): δ 6.45 (d.d, 1H), 5.92 (m, 1H),5.32 (d.q, 1H), 5.23 (d.q, 1H), 4.58 (d.t, 2H), 4.18 (d.d, 1H), 3.97(d.d, 1H), 3.63 (t, 2H), 2.35 (t, 2H), 1.5-1.7 (m, 4H), 1.3 (m, 8H).CIMS (NH₃) m/z 255 (M+H)⁺, 272 (M+NH₄)⁺.

EXAMPLE 4C (2S, 3S, 5S)-3-hydroxy-2, 5-bis(fluorenylmethyloxy)carbonyl!amino-1, 6-diphenylhexane

To a solution of (2S,3S,5S)-2,5-diamino-3-hydroxy-1,6-diphenylhexane(2.84 g, 10.0 mmole; U.S. Pat. No. 5,354,866, issued Oct. 11, 1994) inCH₂ Cl₂ (150 mL) was added Fmoc-OSu (NovaBiochem, 6.75 g, 20.0 mmole)and diisopropypethylamine (3.4 mL, 20 mmole). The solution was stirredat room temperature overnight. The solid formed was collected byfiltration, washed five times with aqueous NaCl solution and dried undervacuum to give the first crop of product. The mother liquor wasconcentrated and the residue taken up in EtOAc (200 mL). The solutionwas washed with saturated NaCl (3×100 mL), then dried and filtered.Solvent evaporation gave additional product. Total yield was 6.13 g(84.2%). ¹ H NMR (DMSO-d₆): δ 1.60 (b.t. 2H), 2.50 (m, 2H), 2.55-2.80(m, 4H), 3.65 (m, 1H), 3.8-4.2 (m, 9H), 7.05-7.45 (m, 18H), 7.60-7.70(m, 4H), 7.86 (d, 4H). FAB-MS m/z 729 (M+H)⁺.

EXAMPLE 4D Allyl 10-{1'- (2'S, 3"S, 5"S)-2", 5"-bis(fluorenylmethyloxy)carbonyl!amino!-1",6"-diphenyl-hex-3-yloxy!ethoxy}decanoate

To a suspension of the product of Example 4C (3.28 g, 4.5 mmole) in CH₂Cl₂ (300 mL) was added allyl 10-vinyloxydecanoate (1.7 g, 6.7 mmole),followed by pyridinium p-toluenesulfonate (0.113 g, 0.45 mmole). Themixture turned clear in about an hour. The reaction was monitoredfrequently by TLC (40% EtOAc-hexane). Additional linker allyl10-vinyloxydecanoate was added (˜20% each time) if necessary untilcomplete conversion of the starting core was observed. The solution wasthen washed with pH7.0 Na₂ HPO₄ (0.1M) buffer (2×150 mL), saturated NaCl(2×100 mL), then dried (MgSO₄). Filtration and solvent evaporation gavea clear oil which was chromatographed on a silica gel column, using 40%EtOAc-hexane solvent to give a foamy solid, 3.0 g, 67%. ¹ H NMR(DMSO-d₆): δ 1.20-1.35 (m, 10H), 1.48 (m, 2H), 1.60-1.70 (m, 4H), 2.32(t, 2H), 2.60-2.95 (m, 4H), 3.30-3.45 (m, 2H), 3.60-3.70 (m, 1H),3.90-4.45 (m, 9H), 4.58 (d.t, 2H), 4.60-4.70 (m, 2H), 4.80-5.00 (m, 1H),5.20-5.35 (d.d.d, 2H), 5.85-6.00 (m, 1H), 7.05-7.45 (m, 18H), 7.60-7.70(m, 4H), 7.85 (d, 4H). FAB-MS (with K⁺) m/z 1021, (M+K)⁺.

EXAMPLE 5 10-{1'- (2'S, 3"S, 5"S)-2", 5"-bis(fluorenylmethyloxy)carbonyl!amino!-1",6"-diphenyl-hex-3-yloxy!ethoxy}decanoic acid

To a solution of the product of Example 4D (4.8 g, 4.9 mmole) in 200 mLof anhydrous THF (Aldrich Gold Label) was added dimedone (6.85 g, 49mmol) and tetrakis(triphenylphosphine)palladium (0) (0.56 g, 0.49mmole). The solution was purged with nitrogen, then stirred undernitrogen at room temperature overnight. The solution was thenconcentrated and the residue was taken up in EtOAc (200 mL) and washedwith pH7.0 Na₂ HPO₄ (0.1M) buffer (2×150 mL). The organic solution wasthen treated repeatedly by mixing with saturated NaHSO₃ (150 mL)followed by vigorous stirring for 15-30 minutes until essentially alldimedone was removed (2-3 treatments required). The organic solution wasthen washed with saturated NaCl (2×150 mL) and worked up routinely. Thecrude product was purified by column chromatography using 50%EtOAc-hexane solvent, which afforded 3.8 g of white solid (84.0%). ¹ HNMR (CDCl₃): δ 1.20-1.35 (m, 10H), 1.48 (m, 2H), 1.65-1.75 (m, 4H), 2.32(t, 2H), 2.60-2.95 (m, 4H), 3.30-3.45 (m, 2H), 3.60-3.70 (m, 1H),3.90-4.45 (m, 9H), 4.60-4.70 (m, 2H), 4.75-4.90 (d.d, 1H), 7.05-7.45 (m,18H), 7.60-7.70 (m, 4H), 7.85 (d, 4H). FAB-MS (with K⁺) m/z 981, (M+K)⁺.

EXAMPLE 6 Coupling of the Diamino Diol Core or the Diamino Alcohol Coreto MBHA Resin

The modified diamino diol core (i.e., the product of Example 3) (5.0mmole, ˜1.5 eq. relative to the resin) or the modified diamino alcoholcore (i.e., the product of Example 5) (5.0 mmole, ˜1.5 eq. relative tothe resin) was dissolved in 10 mL of N-methylpyrrolidone (NMP) and 10 mLof CH₂ Cl₂. To the solution was added diisopropylcarbodiimide (0.79 mL,5.0 mmole) and 0.68 g of HOBt. After stirring for 30-60 min., thesolution was mixed with 5.0 g of NovaBead MBHA resin (NovaBiochem, LaJolla, Calif., substitution: 0.65 mmole/gram) which was pretreated withNMP. The mixture was shaken overnight and then filtered. The resin waswashed with NMP (5 times), NMP/CH₂ Cl₂ (1:1) mixture (5 times) and CH₂Cl₂ (5 times), and vacuum dried. The actual loading level was thendetermined based on the observed weight gain to be 0.5-0.55 mmole pergram.

                  TABLE 1    ______________________________________     ##STR13##                             A. Mono-ol                                       B. Diol                             (X = H)   (X = OH)    Example                  IC.sub.50 (nM).sup.a                                       IC.sub.50 (nM).sup.a    ______________________________________             ##STR14##       <1        9.6    8             ##STR15##       <1        12    9             ##STR16##       <1        3.4    10             ##STR17##       <1        16    ______________________________________     Ph = phenyl     .sup.a The IC.sub.50 against HIV1 protease was measured according to the     method described in U.S. Pat. No. 5,354,866, issued October 11, 1994.

EXAMPLES 7A-10A (X═H) Automated Solid Phase Synthesis of CompoundsContaining the Diamino Alcohol Core

The automated solid phase synthesis was carried out on the Abimed AMS422Multiple Peptide Synthesizer. For the synthesis of each compounds, 60-70mg (˜0.03 mmole) of the diamino alcohol resin (i.e., the product ofExample 6) was added to six separate reaction vessels. The instrumentsoftware was then modified and solutions of the reagents and monomersprepared, all according to the instrument operation manual. A 20 v %solution of piperidine in NMP was used for removal of the Fmoc(deprotection) and activation of carboxylic acids was accomplished by insitu formation of HOBt ester with PyBOP(benzotriazol-1-yloxyltripyrrolidinophosphonium hexafluorophosphate) inthe presence of N-methylmorpholine (NMM). The resins were first washedwith NMP (3×1.5 mL), deprotected by two treatments with the piperidinesolution (20 min. each time) and then washed with NMP (6×1.5 mL); Asolution of Fmoc-Val in NMP (0.3 mL, ˜0.24 mmole), a solution of PyBOPin NMP (0.22 mL, ˜0.22 mmole) and a solution of NMM (0.1 mL, ˜0.4 mmole)were delivered to each of the six reaction vessels. The mixture was thenallowed a coupling time of 60 min. The coupling was then repeated forthe second time (double coupling). Then deprotection and washing wererepeated as described above. To each reaction vessel was then delivereda solution of following carboxylic acids in NMP, respectively:(5-hydantoin)acetic acid, (2-amino-4-thiazole)acetic acid,(3,4,5-trimethoxylphenyl)acetic acid, and (2-pyrimidylthio)acetic acid.A solution of PyBOP in NMP (0.22 mL, ˜0.22 mmole) and a solution of NMM(0.1 mL, ˜0.4 mmole) were delivered to each of the six reaction vessels.The mixture was then allowed a coupling time of 60 min. The coupling wasthen repeated for the second time (double coupling). After the finalcoupling, resins were washed with NMP (6×1.5 mL each reaction vessel)and CH₂ Cl₂ (6×1.5 mL each reaction vessel ) and dried. The resins werethen cleaved by treating the resins with 30% TFA in methylene chloridefor 3 hours . Solutions of the released compounds were then evaporatedin a speedvac and the products characterized by TLC and FAB-MS. The massspectra were consistent with the assigned structures.

EXAMPLES 7B-10B (X═OH) Automated Solid Phase Synthesis of CompoundsContaining the Diamino Diol Core

The automated solid phase synthesis was carried out on the Abimed AMS422Multiple Peptide Synthesizer. For the synthesis of each compound, 60-70mg (˜0.03 mmole) of the diamino diol resin (i.e., product of Example 6)was added to six separate reaction vessels. The instrument software wasthen modified and solutions of the reagents and monomers prepared, allaccording to the instrument operation manual. A 20 v % solution ofpiperidine in NMP was used for removal of the Fmoc (deprotection) andactivation of carboxylic acids was accomplished by in situ formation ofHOBt ester with PyBOP (benzotriazol-1-yloxyltripyrrolidinophosphoniumhexafluorophosphate) in the presence of N-methylmorpholine (NMM). Theresins were first washed with NMP (3×1.5 mL), deprotected by twotreatments with the piperidine solution (20 min. each time) and thenwashed with NMP (6×1.5 mL); A solution of Fmoc-Val in NMP (0.3 mL, ˜0.24mmole), a solution of PyBOP in NMP (0.22 mL, ˜0.22 mmole) and a solutionof NMM (0.1 mL, ˜0.4 mmole) were delivered to each of the six reactionvessels. The mixture was then allowed a coupling time of 60 min. Thecoupling was then repeated for the second time (double coupling). Thedeprotection and washing were repeated as described above. To eachreaction vessel was then delivered a solution of the followingcarboxylic acids in NMP, respectively: 5-hydantoinacetic acid,2-amino-4-thiazoleacetic acid, 3,4,5-trimethoxylphenylacetic acid, and(2-pyrimidylthio)acetic acid. A solution of PyBOP in NMP (0.22 mL, ˜0.22mmole) and a solution of NMM (0.1 mL, ˜0.4 mmole) were delivered to eachof the six reaction vessels. The mixture was then allowed a couplingtime of 60 min. The coupling was then repeated for the second time(double coupling). After the final coupling, resins were washed with NMP(6×1.5 mL each reaction vessel) and CH₂ Cl₂ (6×1.5 mL each reactionvessel) and dried. The resins were then cleaved by treating the resinswith 95% aqueous TFA overnight . Solutions of the released compoundswere then evaporated in a speedvac and the products characterized by TLCand FAB-MS. The mass spectra were consistent with the assignedstructures.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds andprocesses. Variations and changes which are obvious to one skilled inthe art are intended to be within the scope and nature of the inventionwhich are defined in the appended claims.

What is claimed is:
 1. A compound of the formula: ##STR18## wherein R₄and R₅ are independently selected from phenyl, substituted phenyl,loweralkyl and cycloalkyl;L₂ is(a) alkylene, (b) --O--((CH₂)₂ --O)_(m)CH₂ -- wherein m is 1--10 or ##STR19## P₄ and P₅ are the same ordifferent N-protecting groups; and P₆ is hydrogen or a carboxyprotecting group.
 2. A compound according to claim 1 wherein R₄ and R₅are phenyl and L₂ is --(CH₂)_(p) -- wherein p is 1-10 or --O--((CH₂)₂--O)_(m) --CH₂ -- wherein m is 2-6.
 3. A compound according to claim 1wherein R₄ and R₅ are phenyl, L₂ is --(CH₂)₉ -- or --O--((CH₂)₂ --O)₂--CH₂ -- and P₄ and P₅ are independently selected from9-fluorenylmethoxycarbonyl, allyloxycarbonyl and(2-trimethylsilyl)ethoxycarbonyl and P₆ is hydrogen or allyl.
 4. Acompound selected from the group consisting of:Allyl 10-{1'-((2'S, 3"S,5"S)-2",5"-bis(((fluorenylmethyloxy)carbonyl)amino)-1",6"-diphenyl-hex-3-yloxy)ethoxy}decanoateand 10-{1'-((2'S, 3"S, 5"S)-2",5"-bis(((fluorenylmethyloxy)carbonyl)amino)-1",6"-diphenyl-hex-3-yloxy)ethoxy}decanoic acid.